|Publication number||US6509028 B2|
|Application number||US 10/172,455|
|Publication date||21 Jan 2003|
|Filing date||17 Jun 2002|
|Priority date||26 Jun 2000|
|Also published as||CA2413545A1, DE60109164D1, DE60109164T2, EP1296650A2, EP1296650B1, US20020013331, US20020192288, US20030124190, WO2002000195A2, WO2002000195A3|
|Publication number||10172455, 172455, US 6509028 B2, US 6509028B2, US-B2-6509028, US6509028 B2, US6509028B2|
|Inventors||Robert O. Williams, Feng Zhang, John J. Koleng, Gavril W. Pasternak, Yuri A. Kolesnikov|
|Original Assignee||Epicept Corporation|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (55), Non-Patent Citations (18), Referenced by (97), Classifications (33), Legal Events (8)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This is a continuation of application Ser. No. 09/888,466, filed Jun. 25, 2000, now Abandon.
This application claims the benefit of U.S. Provisional patent application Ser. No. 60/222,164, filed Jun. 26, 2000, hereby incorporated by reference herein in its entirety.
The invention relates to methods and compositions for treating the pain associated with mucosal damage, such as inflamation, abrasions, ulcerations, lesions, incisions, and trauma.
The term mucous membrane refers to the moist linings of the buccal cavity, nasal cavity, gastrointestinal tract, respiratory tract, conjunctiva, vagina, colon, urinary bladder, and urethra (Forstner et al., 1973 J. Cell. Sci. 12:585; Peppas et al., 1985 J. Control. Release 2:257; Lehr et al., 1992 J. Control Release 18:249; Spiro, 1970 Ann. Rev. Biochem. 39:599; Lebat-Robert et al., 1979 Path. Biol. 24:241). The normally smooth, moist, and pink buccal mucosa is very sensitive and inflamation or ulceration (oral mucositis) causes severe pain. Dental surgery, such as root canal and tooth extraction can also severely damage the buccal mucosa causing severe pain. Moreover, oral mucositis and dental surgery can induce secondary conditions, such as weight loss and dehydration from reluctance to eat or drink, infection (bacterial, fungal, and viral), fever, nausea, and diarrhea.
Oral mucositis has a variety of causes, for example, bacterial infections, such as streptococci; viral infections, such as herpes simplex virus; fungal infections; side effects of systemic diseases; vitamin deficiency; iron deficiency; cheek biting; mouth breathing; jagged teeth; orthodontic appliances; ill-fitting dentures; excessive use of alcohol or tobacco; thermally-hot foods; spicy foods; and as a side effect of medication. Severely-painful oral mucositis is a symptom endured by almost all chemotherapy patients. Mucositis symptoms peak 7 to 10 days following chemotherapy, and gradually recede over the following two weeks. For a discussion of the causes and symptoms of mucositis, see The Merck Manuel, Fifteenth Edition, Merck Sharp & Dohme Research Laboratories, Rahway, N.J., (1987) pp. 2322-2320.
Topical application of local anesthetics can provide some relief of oral-mucositis and dental-surgery pain but absorption through the mucous membranes occurs rapidly, and pharmaceuticals applied to the mucous membrane for their local effect sometimes cause systemic toxicity (Goodman and Gilman's The Pharmacological Basis of Therapeutics 9th ed. J. G. Harman and L. E. Limird Eds., McGraw-Hill New York 1996 p. 8) especially with the higher doses required for adequate pain relief. Systemic absorption is even more likely when the mucous membrane is ulcerated or inflamed. Thus, with traditional anesthetic compositions for mucositis, e.g., 2 percent lidocaine oral rinse or 5% lidocaine ointment, systemic toxicity limits the dosage and so adequate pain relief is difficult to achieve. Other less toxic pain relieving compositions, such as rinses comprising hydrogen peroxide and sodium bicarbonate are less effective at reducing pain. An additional problem with oral rinses is, that following application, the action of swallowing and saliva reduces the concentration of active agent on the affected area, thus oral rinses comprising local anesthetics have a low duration of activity.
In summation, a long-lasting, non-toxic anesthetic composition effective for amelioration of the severe pain induced by mucosal damage, such as mucositis and dental surgery, is needed.
In one aspect, the invention provides compositions and methods that provide long-lasting local anesthesia and effective pain relief. The compositions of the invention can be topically applied to the affected area, for example, via a dose-metered applicator adapted for spraying or adapted for use with a cannula. When topically applied, the compositions of the invention provide a powerful local-anesthetizing effect, in spite of low anesthetic concentration. Hence, the compositions of the invention provide significant pain relief with low systemic absorption and, therefore, low systemic toxicity. The compositions of the invention, in addition to the ability to remain on the affected area for extended periods, hydrate and soothe.
In one embodiment, the compositions of the invention can be topically applied directly to the affected area to alleviate pain in a subject on any area of a subject's body.
In another embodiment, the compositions of the invention are useful for topical application to a subject's mucous membrane, to induce a long-lasting local-anesthetic effect, thereby relieving pain from mucositis, such as mucosal inflamation, abrasions, ulcerations, and lesions, without significant systemic absorption.
In yet another embodiment, the compositions of the invention are useful for topical application to the site of dental surgery, such as root-canal or tooth-extraction surgery, to induce a long-lasting local-anesthetic effect, thereby relieving the surgical pain, without significant systemic absorption.
In one more embodiment, the invention relates to compositions comprising a mucoadhesive, a local anesthetic or a pharmaceutically-acceptable salt thereof, and an opioid or a pharmaceutically-acceptable salt thereof. In a preferred embodiment, the compositions contain water and are sterile. In a more preferred embodiment, the compositions of the invention, further comprise a chelating agent and a preservative.
In another embodiment, the invention relates to a container adapted for topical application and containing a pharmaceutically-acceptable composition comprising a mucoadhesive, a local anesthetic or a pharmaceutically-acceptable salt thereof, and an opioid or a pharmaceutically-acceptable salt thereof. Preferably, the container is adapted for dose-metered application, such as a dose-metered pump for use with a spray applicator or cannula.
In still another embodiment, the invention relates to a method of inducing local anesthesia in a subject's mucosal membrane by topically applying a pharmaceutically-acceptable composition comprising a local anesthetic or a pharmaceutically-acceptable salt thereof and an opioid or a pharmaceutically-acceptable salt thereof to the subject's mucosal membrane. Preferably, the composition is applied to an area within the subject's buccal or nasal cavity. Preferably, the composition further comprises a mucoadhesive.
In yet another embodiment, the invention relates to a method of inducing local anesthesia in a subject by topically applying a composition comprising a mucoadhesive, a local anesthetic or a pharmaceutically-acceptable salt thereof, and an opioid or a pharmaceutically-acceptable salt thereof to a subject. Preferably, the composition is applied to a mucosal surface of the subject, for example, an area within the subject's buccal or nasal cavity.
These and other features, aspects, and advantages of the invention will become better understood with reference to the following detailed description, examples, and appended claims.
The phrase “pharmaceutically-acceptable salt(s),” as used herein includes but is not limited to salts of acidic or basic groups that may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically-acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, sulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
Compounds included in the present compositions that include an amino moiety may form pharmaceutically-acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds, included in the present compositions, that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. For a review on pharmaceutically-acceptable salts see Berge et al., 1977 J. Pharm. Sci., 66:1, incorporated herein by reference.
As used herein the term “opioid” means all agonists and antagonists of opioid receptors, such as mu (μ), kappa (κ), and delta (δ) opioid receptors and subtypes thereof. For a discussion of opioid receptors and subtypes see Goodman and Gilman's The Pharmacological Basis of Therapeutics 9th ed. J. G. Harman and L. E. Limird Eds., McGraw-Hill New York:1996 pp. 521-555, incorporated herein by reference. The opioid can be any opioid receptor agonist or antagonist known or to be developed. Preferred opioids interact with the μ-opioid receptor, the κ-opioid receptor, or both. Preferably, the opioid is an opioid-receptor agonist.
Examples of suitable opioids for use with the invention include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, benzitramide, nor-binaltorphimine, bremazocine, buprenorphine, butorphanol, clonitazene, codeine, CTOP, DAMGO, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydrocodeine enol acetate, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, diprenorphine, DPDPE, eptazocine, ethoheptazine, ethylketocyclazocine, ethylmethylthiambutene, etonitazene, etorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, lofentanil, loperamide, meperidine, meptazinol, metazocaine, methadone, metopon, morphine, myrophine, nalbuphine, naltrindole, benzoylhydrazone, naltrexone, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, papaverine, pentazocine, phenadoxone, phenazocine, phenoperidine, piminodine, pirtramide, proheptazine, promedol, propiram, propoxyphene, remifentanil, spiradoline, sufentanil, tilidine, U50,488, and U69,593, amiphenazole, cyclazocine, levallorphan, nalmefene, nalorphine, naloxone, and naltrexone or pharmaceutically-acceptable salts thereof, or mixtures thereof.
Examples of peptide opioids include, but are not limited to, Tyr-Gly-Gly-Phe-Leu ([Leu5]enkephalin), Tyr-Gly-Gly-Phe-Met ([Met5]enkephalin), Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln (DynorphinA), Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr (Dynorphin B), Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys (α-Neoendorphin), Tyr-Gly-Gly-Phe-Leu-Arg-Lsy-Tyr-Pro (β-Neoendorphin), Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu (βh-Endorphin), [D-Ala2,MePhe4Gly(ol)5]enkephalin (DAMGO), [D-Pen2,D-Pen5]enkephalin (DPDPE), [D-Ser2,Leu5]enkephalin-Thr6 (DSLET), [D-Ala2,D-Leu5]enkephalin (DADL), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2(CTOP), [D-Ala2,N-MePhe4,Met(O)5-ol]enkephalin (FK-33824), Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2 ([D-Ala2]Deltorphin 1), Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2 ([D-Ala2Glu4]Deltorphin (Deltorphin II)), Tyr-Pro-Phe-Pro-NH2 (Morphiceptin), Tyr-Pro-MePhe-D-Pro-NH2 (PL-017), [D-Ala2,Leu5,Cys6]enkephalin (DALCE) or pharmaceutically-acceptable salts thereof, or mixtures thereof Preferred opioids include morphine, loperamide and loperamide derivatives such as those disclosed in U.S. Pat. Nos. 5,763,445; 5,981,513; 5,869,521; 5,744,458; 5,760,023; 5,798,093; 5,849,762; 5,811,078; 6,004,964; 5,962,477; 5,688,955; 5,888,494; 5,646,151; and 5,667,773 (all of which patents are incorporated by reference herein), or pharmaceutically-acceptable salts thereof, or mixtures thereof. The most preferred opioid is morphine or a pharmaceutically-acceptable salt thereof.
As used herein, the term “local anesthetic” means any drug that provides local numbness or analgesia or any drug that provides a regional blockage of nociceptive pathways (afferent and/or efferent) and that is not an agonist or an antagonist of an opioid receptors. The local anesthetic can be any local anesthetic known or to be developed. Examples of local anesthetics suitable for use with the invention include: ambucaine, amolanone, amylcaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethisoquin, dimethocaine, diperodon, dyclonine, ecogonidine, ecogonine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxyteteracaine, isobutyl p-aminobenzoate, leucinocaine, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, naepaine, octacaine, orthocaine, oxethazaine, parenthoxycaine, phenacaine, phenol, piperocaine, piridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, zolamine, or pharmaceutically-acceptable salts thereof, or mixtures thereof.
The amide and ester type local anesthetics are preferred. Amide type local anesthetics are characterized by an amide functionality, while ester type local anesthetics contain an ester functionality. Preferred amide type local anesthetics, include lidocaine, bupivacaine, prilocaine, mepivacaine, etidocaine, ropivacaine, dibucaine, and pharmaceutically-acceptable salts thereof and mixtures thereof. Preferred ester type local anesthetics include tetracaine, procaine, benzocaine, chloroprocaine, and pharmaceutically-acceptable salts thereof and mixtures thereof. The most preferred local anesthetic is lidocaine. The meaning of “local anesthetic” also encompasses drugs not traditionally associated with local anesthetic properties but which have a local-anesthetic effect, for example, non-narcotic analgesics, such as, acetylsalicylic acid, ketoprofen, piroxicam, diclofenac, indomethacin, ketorolac, Vioxx®, and Celebrex®. Furthermore, in order to improve the effectiveness and tolerance of the present topically-effective therapy, local anesthetics with different pharmacodynamics and pharmacokinetics may be combined in a composition of the invention. A preferred combination of local anesthetics is lidocaine and prilocaine and another preferred combination is lidocaine and tetracaine.
As used herein, the term “local delivery” of a therapeutic, means topical application of the therapeutic to a subject, whereafter a therapeutically-effective amount of the therapeutic is absorbed in the immediate application area, preferably, without significant absorption into the blood stream.
As used herein, a “therapeutically-effective amount” of the compositions of the invention means the amount required to induce a local-anesthetic effect or numbness sufficient to ameliorate pain induced by ulceration, inflamation, or lesions of the buccal or nasal membrane or other mucous membranes or the pain associated with mucosal trauma, such as dental surgery. Preferably, the active agents of the composition are not absorbed systemically.
As used herein, the term “subject” means any animal, preferably a mammal, more preferably a human.
As used herein the term “mucoadhesive” means a natural or synthetic substance, e.g., gels, pastes, macromolecules, polymers, and oligomers, or mixtures thereof, that can adhere to a subject's mucous membrane for a period of time sufficient to locally deliver a therapeutically-effective amount of a composition of the invention to a subject. Adhesion of mucoadhesives to the mucous membrane occurs primarily via secondary chemical bonds, such as hydrogen bonding and Van der Waal forces (Tabor et al., 1977 J. Colloid Interface Sci. 58:2 and Good 1977 J. Colloid Interface Sci. 59:398). Mucoadhesive substances often form viscous aqueous solutions. The composition itself does not need to be mucoadhesive, as long as it can form a mucoadhesive gel upon on the contact with the mucous membrane. For example, gellan gum itself is a very weak mucoadhesive. On contact with the buccal membrane, gellan gum can interact with the ions in the mucous membrane and form an adhesive gel layer. According to the invention, mucoadhesives possess binding properties that may be distinguished from non-mucoadhesives by comparing the degree of adhesion to a mucosal surface. For example, comparison of a potential mucoadhesive with a control emulsion of comparable viscosity prepared without mucoadhesive properties, e.g., a starch solution. At similar viscosities, the emulsion prepared with the mucoadhesive will bind to the mucosal surface more strongly than will the control emulsion, preferably at least 25% greater mucosal binding than the control emulsion, more preferably at least 50% greater, still more preferably at least 100% greater mucosal binding. Either mechanical binding to mucous membrane per se or the degree of biological effect of a drug delivered may be used as a measurement parameter for mucoadhesion. This test may be used to distinguish preferred mucoadhesives. Substances can be screened for their ability to be used as mucoadhesives for local delivery of compositions of the invention according to the methodology described in Smart et al., 1982 J. Pharm. Pharmacol. 34:70P and Smart et al., 1984 J. Pharm. Pharmacol. 36:295, which methodology comprises estimating values of adhesive strength between the substance and the mucous membrane. Preferably, the mucoadhesive is water soluble, such that at least 1% by weight of the mucoadhesive is soluble in water at 25° C. In a preferred embodiment, the mucoadhesive will exhibit non-Newtonian fluid properties, i.e., the viscosity decreases with increasing shear forces. Accordingly, the viscosity of the composition can be modulated by altering the shear forces present when the composition is applied to a surface. A composition with non-Newtonian fluid properties, becomes less viscous when shaken or atomized, then, upon standing, returns to its original viscosity.
Examples of mucoadhesives for use in the present invention include, but are not limited to, pectin, alginic acid, chitosan, hyaluronic acid, polysorbates, such as polysorbate-20, -21, -40, -60, -61, -65, -80, -81, -85; poly(ethyleneglycol), such as PEG-7, -14, -16, -18, -55, -90, -100, -135, -180, -4, -240, -6, -8, -9, -10, -12, -20, or -32; oligosaccharides and polysaccharides, such as gellan, carrageenan, xanthan gum, gum Arabic, and dextran; cellulose esters and cellulose ethers; modified cellulose polymers, such as carboxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl ethylcellulose; polyether polymers and oligomers, such as polyoxyethylene; condensation products of poly(ethyleneoxide) with various reactive hydrogen containing compounds having long hydrophobic chains (e.g. aliphatic chains of about 12 to 20 carbon atoms), for example, condensation products of poly(ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols; polyether compounds, such as poly(methyl vinyl ether), polyoxypropylene of less than 10 repeating units; polyether compounds, such as block copolymers of ethylene oxide and propylene oxide; mixtures of block copolymers of ethylene oxide and propylene oxide with other excipients, for example, pluronic lethicin organogel (see 1997 International Journal of Pharmaceutical Compounding 1:71); poly(vinyl alcohol); polyacrylamide; hydrolyzed polyacrylamide; poly(vinyl pyrrolidone); poly(methacrylic acid); poly(acrylic acid) or cosslinked polyacrylic acid, such as carbomer, i.e., a homopolymer of acrylic acid crosslinked with either an allyl ether of pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene (e.g., Acrisint® 400, 410, or 430 commercially available from 3V Inc. Weehawkin, N.J.); Orabase® (i.e., a mixture of gelatine, pectin and sodium carboxymethyl cellulose in a plasticized hydrocarbon gel, commercially available from Hoyt laboratories, Needhm, Mass.); Carafate® (sulfated sucrose and aluminum hydroxide, commercially available from Marion Laboratories, Inc., Kansas City, Mont.). The block copolymers of ethylene oxide and propylene oxide are particularly preferred. Preferred block copolymers of ethylene oxide and propylene oxide are represented by formula I below:
Wherein x is an integer having an average value within the range of from about 2 to about 128; y is an integer having an average value within the range of from about 14 to about 80; and z is an integer having an average value within the range of from about 2 to about 128. Preferably, x and y are about equal. More preferred block copolymers of ethylene oxide and propylene oxide, falling within the genus represented by formula I, are shown in Table 1 below.
value of x
value of y
value of z
Pluronic ® L-31
Calgene Nonionic ® 1042-L
Calgene Nonionic 1063-L
Calgene Nonionic 1072-L
Calgene Nonionic 1075-P
Calgene Nonionic 1094-P
The most preferred mucoadhesive for use with the invention is poloxamer 407. The block copolymers of ethylene oxide and propylene oxide sold under the trade name Pluronic are commercially available, e.g., BASF (Washington, N.J.). The block copolymers of ethylene oxide and propylene oxide sold under the trade name Calgene are commercially available, e.g., Calgene Chemical, Inc. Skokie, Ill.
Preferably, when administered to a subject, the compositions of the invention are sterile.
Suitable preservatives include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimide, dequalinium chloride, and cetylpyridinium chloride; mercurial agents, such as phenylmercuric nitrate, phenylmercuric acetate, and thimerosal; alcoholic agents, for example, chlorobutanol, phenylethyl alcohol, and benzyl alcohol; antibacterial esters, for example, esters of para-hydroxybenzoic acid; and other anti-microbial agents such as chlorhexidine, chlorocresol, and polymyxin.
Suitable chelating agents include, but are not limited to, deferoxamine, ditiocarb sodium, edetate calcium disodium, edetate disodium, edetate sodium, edetate trisodium, penicillamine, pentetate calcium trisodium, pentetic acid, succimer, trientin.
Preferably, the pH of the composition is within the range of from about 2 to about 9, more preferably, about 3 to about 7, even more preferably about 4 to about 5, and optimally about 4.5. Under acidic conditions, protonation permits H-bonding between the polymer and the mucin network, resulting in enhanced retention of the polymer in contact with a mucosal surface. The pH can be adjusted by adding an aqueous acid or base, dropwise to the composition until the desired pH is obtained. Any physiologically acceptable pH adjusting acids, bases or buffers are acceptable, e.g., acids, such as acetic, boric, citric, lactic, phosphoric, hydrochloric; bases, such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, THAM (trishydroxymethylaminomethane); and buffers such as citrate/dextrose, sodium bicarbonate, ammonium chloride and mixtures thereof, preferably, 0.1 normal hydrochloric acid for a pH of less than 7 and 0.1 normal aqueous sodium hydroxide for a pH of greater than 7.
The composition of the invention can also comprise NMDA receptor antagonists including, but not limited to, dextromethorphan, dextrorphan, ketamine, pyroloquinolin quinone, cis-4-(phosphonomethyl)-2-piperidine carboxylic acid, MK801, memantine, D-methadone, or pharmaceutically-acceptable salts thereof.
The compositions of the invention can also include other excipients and pharmaceuticals. Examples of excipients that can be included in the topical compositions of the invention include, but are not limited to, antibiotics, analgesics, antifungal agents, non-steroidal anti-inflammatory agents, anti-tussive agents, expectorants, glucocorticoids, vitamins, anti-oxidants, flavoring agents, sweetening agents, iso-osmotic agents, moisturizers, emollients, buffering agents, solubilizing agents, penetration agents, protectants, surfactants, and propellants, and other conventional systemic or topical pain relief therapies, analgesics, and pharmaceuticals.
Examples of suitable antibiotics include, but are not limited to, aminoglycoside antibiotics; such as apramycin, arbekacin, bambermycins, butirosin, dibekacin, neomycin, neomycin undecylenate, netilmicin, paromomycin, ribostamycin, sisomicin, and spectinomycin; amphenicol antibiotics, such as azidamfenicol, chloramphenicol, florfenicol, and thiamphenicol; ansamycin antibiotics, such as rifamide and rifampin; carbacephems, such as loracarbef; carbapenems, such as biapenem and imipenem; cephalosporins, such as cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefozopran, cefpimizole, cefpiramide, and cefpirome; cephamycins, such as cefbuperazone, cefmetazole, cefminox; monobactams, such as aztreonam, carumonam, and tigemonam; oxacephems, such as flomoxef, and moxalactam; penicillins, such as amdinocillin, amdinocillin pivoxil, amoxicillin, bacampicillin, benzylpenicillinic acid, benzylpenicillin sodium, epicillin, fenbenicillin, floxacillin, penamccillin, penethamate hydriodide, penicillin o-benethamine, penicillin 0, penicillin V, penicillin V benzathine, penicillin V hydrabamine, penimepicycline, and phencihicillin potassium; lincosamides, such as clindamycin, and lincomycin; macrolides, such as azithromycin, carbomycin, clarithomycin, dirithromycin, erythromycin, erythromycin acistrate; polypeptides, such as amphomycin, bacitracin, capreomycin, colistin, enduracidin, and enviomycin; tetracyclines, such as apicycline, chlortetracycline, clomocycline, and demeclocycline; 2,4-diaminopyrimidines, such as brodimoprim; nitrofurans, such as furaltadone, and furazolium chloride; quinolones and analogs, such as cinoxacin, ciprofloxacin, clinafloxacin, flumequine, and grepagloxacin; sulfonamides, such as acetyl sulfamethoxypyrazine, benzylsulfamide, noprylsulfamide, phthalylsulfacetamide, sulfachrysoidine, and sulfacytine; sulfones, such as diathymosulfone, glucosulfone sodium, and solasulfone; and others, such as cycloserine, mupirocin, tuberin.
Examples of suitable analgesics include, but are not limited to, aceclofenac, acetaminophen, acetaminosalol, acetanilide, acetylsalicylsalicylic acid, alclofenac, alminoprofen, aloxiprin, aluminum bis(acetylsalicylate), aminochlorthenoxazin, 2-amino-4-picoline, aminopropylon, aminopyrine, ammonium salicylate, amtohnetin guacil, antipyrine, antipyrine salicylate, antrafenine, apazone, aspirin, benorylate, benoxaprofen, benzpiperylon, benzydamine, bermoprofen, bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate, bucetin, bufexamac, bumadizon, butacetin, calcium acetylsalicylate, carbamazepine, carbiphene, carsalam, chlorthenoxazin(e), choline salicylate, cinchophen, ciramadol, clometacin, clonixin, cropropamide, crotethamide, dexoxadrol difenamizole, difiunisal, dihydroxyaluminum acetylsalicy, late, dipyrocetyl, dipyrone, emorfazone, enfenamic acid, epirizole, etersalate, ethenzamide, ethoxazene, etodolac, felbinac, fenoprofen, floctafenine, flufenamic acid, fluoresone, flupirtine, fluproquazone, flurbiprofen, fosfosal, gentisic acid, glafenine, ibufenac, imidazole salicylate, indomethacin, indoprofen, isofezolac, isoladol, isonixin, ketoprofen, ketorolac, p-lactophcnetide, lefetamine, lomoxicam, loxoprofen, lysine acerylsalicylate, magnesium acetylsalicylate, methotrimeprazine, metofoline, mofezolac, morazone, morpholine salicylate naproxen, nefopam, nifenazone, 5′-nitro-2′-propoxyacetanilide, parsalmide, perisoxal, phenacetin, phenazopyridine hydrochloride, phenocoll, phenopyrazone, phenyl acetylsalicylate, phenyl salicylate, phenyramidol, pipebuzone, piperylone, propacetamol, propyphenazone, ramifenazone, rimazolium metilsulfate, salacetamide, salicin, salicylamide, salicylamide o-acetic acid, salicylsulfuric acid, salsalate, salverine, simetride, sodium salicylate, suprofen, talniflumate, tenoxicam, terofenamate, tetrandrine, tinoridine, tolfenamic acid, tramadol, tropesin, viminol, xenbucin, and zomepirac.
Examples of suitable antifungal agents include, but are not limited to, polyenes, such as amphotericin b, candicidin, mepartricin, natamycin, and nystatin; allylamines, such as butenafine, and naftifine; imidazoles, such as bifonazole, butoconazole, chlordantoin, flutrimazole, isoconazole, ketoconazole, and lanoconazole; thiocarbamates, such as tolciclate, tolindate, and tolnaftate; triazoles, such as fluconazole, itraconazole, saperconazole, and terconazole; and others, such as bromosalicylchloranilide, buclosamide, calcium propionate, chlorphenesin, and ciclopirox; and others, such as azaserine, griseofulvin, oligomycins, neomycin undecylenate, pyrrolnitrin, siccanin, tubercidin, viridin.
Examples of suitable non-steroidal anti-inflammatory agents include, but are not limited to, aminoarylcarboxylic acid derivatives, such as enfenamic acid, etofenamate, flufenamic acid, isonixin, meclofenamic acid, mefenamic acid, niflumic acid, talniflumate, terofenamate, and tolfenamic acid; arylacetic acid derivatives, such as aceclofenac, acemetacin, alclofenac, amfenac, amtolmetin guacil, bromfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etodolac, felbinac, fenclozic acid, fentiazac, glucametacin, ibufenac, indomethacin, isofezolac isoxepac, lonazolac, metiazinic acid, mofezolac, oxametacine, pirazolac, proglumetacin, sulindac, tiaramide, tolmetin, tropesin, and zomepirac; arylbutyric acid derivatives, such as bumadizon, butibufen, fenbufen, xenbucin; arylcarboxylic acids, such as clidanac, ketorolac, tinoridine; arylpropionic acid derivatives, such as alminoprofen, benoxaprofin, bermoprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, piketoprofin, pirprofen, pranoprofen, protizinic acid, suprofen, tiaprofenic acid, ximoprofen, and zaltoprofen; pyrazoles, such as difenamizole, and epirozole; pyrazolones, such as apazone, benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone, phenylbutazone, pipebuzone, propyphenazone, ramifenazone, suxibuzone, and thiazolinobutazone; salicylic acid derivatives, such as acetaminosalol, aspirin, benorylate, bromosaligenin, calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholine salicylate, 1-naphtyl salicylate, olsalazine, parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide, salicylamide o-acetic acid, salicylsulfuric acid, salsalate, sulfasalazine; thiazinecarboxamides, such as ampiroxicam, droxicam, isoxicam, lomoxicam, piroxicam, and tenoxicam; and others, such as ε-acetamidocaproic acid, s-adenosylmethionine, 3-amino-4-hydroxybutytic acid, amixetrine, bendazac, benzydamine, α-bisabolol, bucololome, difenpiramide, ditazol, emorfazone, fepradinol, guaiazulene, nabumetone, nimesulide, oxaceprol, paranyline, perisoxal, proquazone, superoxide dismutase, tenidap, and zilenton.
Examples of suitable antitussive agents include, but are not limited to, alloclamide, amicibone, benproperine, benzonatate, bibenzonium bromide, bromoform, butamirate, butethamate, caramiphen ethanedisulfonate, carbetapentane, chlophedianol, clobutinol, cloperastine, codeine, codeine methyl bromide, codeine n-oxide, codeine phosphate, codeine sulfate, cyclexanone, dimethoxanate, dropropizine, drotebanol, eprazinone, ethyl dibunate, ethylmorphine, fominoben, guaiapate, hydrocodone, isoaminile, levopropoxyphene, morclofone, narceine, mormethadone, noscapine, oxeladin, oxolamine, pholcodine, picoperine, pipazethate, piperidione, prenoxdiazine hydrochloride, racemethorphan, sodium dibunate, tipepidine, and zipeprol.
Example of suitable expectorants include, but are not limited to, ambroxol, ammonium bicarabonate, ammonium carbonate, bromhexine, calcium iodide, carbocysteine, guaiacol, guaiacol benzoate, guaiacolcarbonate, guaiacol phosphate, guaifenesin, guaithylline, hydriodic acid, iodinated glycerol, potassium guaiacolsulfonate, potassium iodide, sodium citrate, sodium iodide, storax, terebene, terpin, and trifolium.
Suitable glucocorticoids include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, flucortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, and triamcinolone hexacetonide.
Suitable vitamins include, but are not limited to calcipotriene, calcitriol, ergosterol, 1α-hydroxycholecalciferol, vitamin D2+, vitamin D3+, ascorbic acid, calcium ascorbate, nicotinamide ascorbate, sodium ascorbate, α-carotene, β-carotene, δ-carotene, vitamin A, cobamamide, folic acid, hydroxocobalamin, sodium folate, vitamin B12, menadiol, menadione, menadoxime, menaquinones, phylloquinone, vitamin K5+, inositol, αtocopherol, γ-tocopherol, γ-tocopherol, vitamin E, vitamin E acetate, and vitamin U.
Examples of suitable anti-oxidants include, but are not limited to, ascorbic acid, sodium ascorbate, sodium bisulfite, sodium thiosulfate, 8-hydroxy quinoline, and N-acetyl cysterine.
Examples of suitable flavoring agents include, but are not limited to, oil of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, and orange, and methyl salicylate.
Examples of suitable sweetening agents include, but not limited to, sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, AMP (aspartyl phenyl alanine, methyl ester), and saccharine.
The compositions of the present invention optionally can include an iso-osmotic agent which functions to prevent irritation of the mucosa by the composition. Examples of pharmaceutically-acceptable iso-osmotic agents which can be used include sodium chloride, dextrose, and calcium chloride.
Preferably, the amount of local anesthetic in the composition is within the range of from about 0.005 percent to about 2 percent of the total weight of the composition, more preferably, of from about 0.01 percent to about 0.5 percent of the total weight of the composition.
For treatment of oral mucositis, a preferred concentration of local anesthetic is from about 0.02 percent to about 0.1 percent of the total weight of the composition, more preferably, about 0.04 percent to about 0.08 percent. For treatment of more painful conditions, such as dental surgery (e.g., tooth extraction or root canal), a preferred concentration of local anesthetic is from about 0.1 percent to about 0.4 percent of the total weight of the composition, more preferably, about 0.2 percent to about 0.3 percent.
Preferably, the amount of opioid in the composition is within the range of from about 0.005 percent to about 3 percent of the total weight of the composition, more preferably, of from about 0.01 percent to about 2 percent, still more preferably, of from about 0.05 percent to about 1 percent of the total weight of the composition. For treatment of oral mucositis, a preferred concentration of opioid is from about 0.1 percent to about 0.3 percent of the total weight of the composition. For treatment of more painful conditions, such as dental surgery, a preferred concentration of opioid is from about 0.3 percent to about 0.8 percent of the total weight of the composition, more preferably, about 0.4 percent to about 0.5 percent.
Preferably, the amount of mucoadhesive in the composition is within the range of from about 0.1 percent to about 40 percent of the total weight of the composition, more preferably, of from about 10 percent to about 30 percent, and optimally, of from about 15 percent to about 25 percent of the total weight of the composition.
Preferably, the amount of water in the composition is within the range of from about 95 percent to about 10 percent of the total weight of the composition, more preferably, of from about 90 percent to about 50 percent, and optimally, of from about 85 percent to about 75 percent of the total weight of the composition.
When a chelating agent is used, preferably, it is present in an amount within the range of from about 0.005 percent to about 1 percent of the total weight of the composition, more preferably, of from about 0.01 percent to about 0.5 percent, still more preferably, of from about 0.05 percent to about 0.2 percent of the composition.
When a preservative is used, preferably, it is present in an amount within the range of from about 0.0001 percent to about 0.2 percent of the total weight of the composition, more preferably, of from about 0.0005 percent to about 0.1 percent, and optimally, of from about 0.001 percent to about 0.05 percent of the total weight of the composition.
To relieve pain from mucositis, the compositions or the invention are topically applied directly to the affected area. The compositions of the invention can be applied to the affected area of the mucous membrane in any conventional manner well known in the art, for example, as a mist via an aerosol applicator, by cannula, via a patch, by a dropper, or by an applicator stick, preferably as a mist, more preferably as a metered-dose mist. A mist can be sprayed onto the area to be treated via an aerosol container, pressurized or non-pressurized, preferably a non-pressurized pump. For more specific applications, a cannula can be used. The cannula can be attached to a pressurized or non-pressurized pump, preferably a non-pressurized pump.
A suitable non-pressurized pump for application of compositions of the invention can comprise a container, a valve, an actuator, and optionally a dip tube. The non-pressurized pump's container can be metal, such as a tin plated steel or aluminum, glass, or plastic. The valve's primary purpose is to regulate the flow of product from the container. It provides a means of discharging the desired amount. Suitable spray valves are described in Remington's Pharmaceutical Sciences 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, Pa., 1990 pp. 1703-1704, incorporated herein by reference. The actuator provides a means for releasing the contents from a pressurized container. Suitable actuators are described in Remington's Pharmaceutical Sciences 18th Edition, ed. Alfonso Gennaro, Mack Publishing Co. Easton, Pa., 1990 pp. 1704-1705, incorporated herein by reference.
Preferably, the metered pump is a VP 7 Screw-On Pump (90 μl, 18/415) commercially available from Valois of America, Inc. (Greenwich, Conn.). The VP 7 screw-on pump is manufactured from polyethylene and polypropylene. It is designed in a way such that the hydraulically opening clapper eliminates the use of any elastomeric gaskets in contact with the product. The pump has an annular dosing chamber, which fills only at the full return of the actuator to ensure full dosing and precision.
The preferred actuator is the 132C-BL GP4 BL long throat actuator commercially available from Valois Pharmaceuticals, Inc. Preferably, the actuator is manufactured from polyethylene and polypropylene and, preferably, contains a captive insert to provide a well-atomized spray pattern. The captive insert also reduces the dead volume in the actuator.
When a cannula is used, for application to a specific area rather than as a spray, the preferred actuator is a stainless-steel cannula of about 73 mm in length, for example, the 215 stainless-steel cannula commercially available from Valois Pharmaceuticals, Inc. Polyethylene or polypropylene cannulas can also be used.
The compositions of the invention can also be delivered to the buccal or nasal cavity via a patch that is applied adjacent to the area of skin to be treated. As used herein a “patch” comprises at least a composition of the invention and a covering layer, such that, the patch can be placed over the area to be treated. Preferably, the patch is designed to maximize local delivery and to minimize absorption into the circulatory system, reduce lag time, promote uniform absorption, and reduce mechanical rub-off. Suitable patches are described in Transdermal and Topical Drug Delivery Systems, Interpharm Press, Inc. p. 249-297, incorporated herein by reference. Suitable patches for buccal delivery of compositions of the invention is disclosed in U.S. Pat. Nos. 5,713,852 and 4,900,552, both of which are incorporated herein by reference.
The amount of the composition of the invention applied to the buccal or nasal passages will vary depending on the particular mucoadhesive, local anesthetic, and opioid used; the nature and severity of the mucosal lesion or inflamation being treated, and the subject. The composition should be applied to the affected area as recommended by a physician, preferably, as needed by the patient to relieve pain. For example, a dose of about 0.05 mg to about 4 mg morphine sulfate and 0.02 mg to about 3 mg of lidocaine hydrochloride in about 0.5 g to about 3 g of composition can be delivered to the affected area. When applying as a spray, a dose of about 2 mg morphine sulfate and about 1 mg lidocaine hydrochloride in about 1.5 g of composition can be delivered to the affected area. For more precise applications by cannula, a dose of about 2 mg morphine sulfate and about 1 mg lidocaine hydrochloride in about 0.4 g of composition can be delivered to the affected area.
In a preferred embodiment of administration, the dose is delivered with a spray actuator in about 8 to about 20 separate spray shots, more preferably about 16 spray shots, wherein each spray shot weighs about 50 mg to about 150 mg, more preferably about 100 mg. In another preferred embodiment of administration, the dose is delivered via cannula in about 4 spray shots, wherein each spray shot weighs about 100 mg.
Although the present invention has been described in considerable detail with reference to certain preferred embodiments, other embodiments are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description of the preferred embodiments contained herein.
The following examples are provided for illustrative purposes only and are not to be construed as limiting the invention's scope in any manner.
A composition of the present invention is described in Table 2 below.
Morphine sulfate pentahydrate
Lidocaine hydrochloride monohydrate
Edetate disodium dihydrate
(50% aqueous solution)
0.1 N aqueous hydrochloric acid
Morphine sulfate pentahydrate (122.6 mg), lidocaine (65.4 mg) hydrochloride monohydrate, and edetate disodium dihydrate (100 mg ) were dissolved in 80 g of sterile water. The resulting solution was cooled to 10° C. in an ice bath and poloxmer 407 (20 g) was slowly added with mixing until the Poloxmer 407 completely dissolved. The solution was maintained at about 10° C. until the foam collapsed. About 4 g of the solution was added to a 5 ml vial and a Valois VP7/90 18/415 pump was screwed onto the vial and refrigerated at 4° C. for 30 minutes. The vial was removed from the refrigerator and the metered pump was primed using the Valois 165 actuator. The Valois 165 actuator was removed and the filled vial was stored at 4° C. until the foam collapsed. The vial was removed from the refrigerator and kept at room temperature (25° C.) until the contents gelled.
The viscosity of the above-prepared oral spray was measure using a Brookfield RVT viscometer. At 30° C. the viscosity was 82,666 cps (averaged over three determinations) and at 40° C. the viscosity was 95,666 cps (averaged over three determinations).
The composition can be applied as follows. Attach the long throat actuator to the metering pump and store the unit at 4° C. for at least 30 minutes. To prime the pump (7-8 sprays), with actuator in the up position, press the actuator firmly and quickly to spray into a waste container, hold the actuator for about one second when it is in the pressed position following each spray. With actuator in the up position, press the actuator firmly and quickly to spray onto the surface of the subject to be treated. Hold the actuator for two to three seconds when it is in the pressed position following each spray. Apply a total of 16 spray shots of for a total application of about 2 mg morphine sulfate and about 1 mg lidocaine hydrochloride in about 1.5 g of composition. Once the spray makes contact with the mucous membrane at body temperature, the liquid will form a viscous mucoadhesive gel. If it takes more than 90 seconds to apply 16 spray shots, store the unit at 4° C. for 10 minutes to cool the content before further usage.
A second composition of the present invention is described in Table 2 below.
Morphine sulfate pentahydrate
Lidocaine hydrochloride monohydrate
Edetate disodium dihydrate
(50% aqueous solution)
0.05 N aqueous hydrochloric acid
Morphine sulfate pentahydrate (490.48 mg), lidocaine (261.6 mg) hydrochloride monohydrate, and edetate disodium dihydrate (100 mg) were dissolved in 80 g of sterile water. The resulting solution was cooled to 10° C. in an ice bath and poloxmer 407 (20 g) was slowly added with mixing until the Poloxmer 407 completely dissolved. The solution was maintained at about 10° C. until the foam collapsed. About 4 g of the solution was added to a 5 ml vial and a Valois VP7/90 18/415 pump was screwed onto the vial and refrigerated at 4° C. for 30 minutes. The vial was removed from the refrigerator and the metered pump was primed using the Valois 165 actuator. The Valois 165 actuator was removed and the filled vial was stored at 4° C. until the foam collapsed. The vial was removed from the refrigerator and kept at room temperature (25° C.) until the contents gelled.
The viscosity of the above-prepared oral spray was measure using a Brookfield RVT viscometer. At 30° C. the viscosity was 81,000 cps (averaged over three determinations) and at 40° C. the viscosity was 94,333 cps (averaged over three determinations).
The composition can be applied using a long-throat actuator as described above (for spray application) or by cannula (for application to a specific area). A total of 4 spray shots is recommended. For application to a specific area by cannula rather than as a spray, the preferred actuator is a stainless-steel cannula of about 73 mm in length, for example, the 215 stainless-steel cannula commercially available from Valois Pharmaceuticals, Inc.
The foregoing has outlined rather broadly the more pertinent and important features of the present invention. While it is apparent that the invention disclosed herein is well calculated to fulfill the objects stated above, it will be appreciated that numerous modifications and embodiments may be devised by those skilled in the art. Therefore, it is intended that the appended claims cover all such modifications
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US4051234||29 Apr 1976||27 Sep 1977||The Procter & Gamble Company||Oral compositions for plaque, caries, and calculus retardation with reduced staining tendencies|
|US4226848||2 Mar 1979||7 Oct 1980||Teijin Limited||Method and preparation for administration to the mucosa of the oral or nasal cavity|
|US4704406||24 Jun 1986||3 Nov 1987||Klinge Pharma Gmbh||Sprayable pharmaceutical composition for topical use|
|US4764378||10 Feb 1986||16 Aug 1988||Zetachron, Inc.||Buccal drug dosage form|
|US4855142||17 Feb 1988||8 Aug 1989||Ciba-Geigy Corporation||Pharmaceutical plaster|
|US4900552||30 Mar 1988||13 Feb 1990||Watson Laboratories, Inc.||Mucoadhesive buccal dosage forms|
|US5219861||10 Jun 1991||15 Jun 1993||Chugai Seiyaku Kabushiki Kaisha||6 β-Thiomorphine derivatives|
|US5225196||7 Jan 1991||6 Jul 1993||Columbia Laboratories, Inc.||Bioadhesive compositions and methods of treatment therewith|
|US5292362||9 Jul 1991||8 Mar 1994||The Trustees Of Columbia University In The City Of New York||Tissue bonding and sealing composition and method of using the same|
|US5395318||24 Jan 1994||7 Mar 1995||Kaprelian; Edward K.||Method and apparatus for wound treatment|
|US5458879||30 Sep 1994||17 Oct 1995||The Procter & Gamble Company||Oral vehicle compositions|
|US5460826||27 Jun 1994||24 Oct 1995||Alza Corporation||Morphine therapy|
|US5496811||5 Jan 1993||5 Mar 1996||Pharmos Corp.||Submicron emulsions as ocular drug delivery vehicles|
|US5578315||1 Dec 1993||26 Nov 1996||Rutgers, The State University Of New Jersey||Mucosal adhesive device for long-acting delivery of pharmaceutical combinations in oral cavity|
|US5589840||24 May 1995||31 Dec 1996||Seiko Epson Corporation||Wrist-type wireless instrument and antenna apparatus|
|US5593695||24 May 1995||14 Jan 1997||Alza Corporation||Morphine therapy|
|US5629011||4 Feb 1993||13 May 1997||Danbiosyst Uk Limited||Composition for nasal administration|
|US5635540||9 Dec 1994||3 Jun 1997||The University Of Virginia Patent Foundation||Stabilized topical pharmaceutical preparations|
|US5662924||7 Jun 1995||2 Sep 1997||Smith & Nephew Plc||Wound dressing|
|US5667773||12 Mar 1996||16 Sep 1997||Adolor Corporation||Film-forming compositions of antihyperalgesic opiates and method of treating hyperalgesic conditions therewith|
|US5667805||4 Oct 1996||16 Sep 1997||Alza Corporation||Morphine therapy|
|US5686112||20 Dec 1995||11 Nov 1997||Apl-American Pharmed Labs, Inc.||Single dosage semi-solid topical pharmaceutical forms for transdermal therapy|
|US5713852||7 Jun 1995||3 Feb 1998||Alza Corporation||Oral dosage and method for treating painful conditions of the oral cavity|
|US5744458||23 Jul 1997||28 Apr 1998||Adolor Corporation||Kappa agonist compounds and pharmaceutical formulations thereof|
|US5747060||26 Mar 1996||5 May 1998||Euro-Celtique, S.A.||Prolonged local anesthesia with colchicine|
|US5760023||14 Jul 1997||2 Jun 1998||Adolor Corporation||Kappa agonist anti-pruritic pharmaceutical formulations and method of treating pruritus therewith|
|US5798093||14 Jul 1997||25 Aug 1998||Adolor Corporation||Spray formulations of antihyperalgesic opiates and method of treating topical hyperalgesic conditions and pruritus therewith|
|US5811078||14 Mar 1997||22 Sep 1998||Adolor Corporation||Spray formulations of antihyperalgesic opiates and method of treating topical hyperalgesic conditions therewith|
|US5814330||10 May 1995||29 Sep 1998||Janssen Pharmaceutica, N.V.||Mucoadhesive emulsions containing cyclodextrin|
|US5817625||9 Jan 1995||6 Oct 1998||Oncogene Science, Inc.||Methods of prevention of oral mucositis with transforming growth factor beta|
|US5834478||12 Sep 1997||10 Nov 1998||Pfizer Inc.||Morphinan hydroxamic acid compounds|
|US5846971||20 Jun 1997||8 Dec 1998||Schering Corporation||Oral antifungal composition|
|US5849322||23 Oct 1995||15 Dec 1998||Theratech, Inc.||Compositions and methods for buccal delivery of pharmaceutical agents|
|US5849761||12 Sep 1995||15 Dec 1998||Regents Of The University Of California||Peripherally active anti-hyperalgesic opiates|
|US5849762||14 Jul 1997||15 Dec 1998||Adolor Corporation||Peripherally acting anti-pruritic opiates|
|US5855907||24 Mar 1997||5 Jan 1999||Peyman; Gholam A.||Method of treatment of migraine|
|US5866143||15 Oct 1996||2 Feb 1999||El Khoury And Stein, Ltd.||Topical application of opioid drugs such as morphine for relief of itching and skin disease|
|US5876744||28 Jul 1995||2 Mar 1999||Lifegroup S.P.A.||Highly bioadhesive and mucoadhesive compositions containing polyvinyl alcohol, polycarbophil and biopolymer for the treatment of skin conditions and as vehicles for active ingredients|
|US5885597||1 Oct 1997||23 Mar 1999||Medical Research Industries,Inc.||Topical composition for the relief of pain|
|US5900247||27 Dec 1996||4 May 1999||Adir Et Compagnie||Mucoadhesive pharmaceutical composition for the controlled release of active principles|
|US5906810||30 Jul 1996||25 May 1999||Turner; Robert E.||Formulations and uses thereof in the prevention and treatment of oral lesions|
|US5908846||11 Nov 1991||1 Jun 1999||Pharmacia & Upjohn Ab||Topical compositions for transdermal delivery of prodrug derivatives of morphine|
|US5922340||16 Sep 1996||13 Jul 1999||Children's Medical Center Corporation||High load formulations and methods for providing prolonged local anesthesia|
|US5942243||12 May 1998||24 Aug 1999||Polytherapeutics, Inc.||Mucoadhesive compositions for administration of biologically active agents to animal tissue|
|US5942251||17 Apr 1998||24 Aug 1999||Merkus; Franciscus W. H. M.||Pharmaceutical compositions for intranasal administration of dihydroergotamine|
|US5948430||1 Aug 1997||7 Sep 1999||Lts Lohmann Therapie-Systeme Gmbh||Water soluble film for oral administration with instant wettability|
|US5955097||18 Oct 1996||21 Sep 1999||Virotex Corporation||Pharmaceutical preparation applicable to mucosal surfaces and body tissues|
|US5958379||28 Sep 1995||28 Sep 1999||Mika Pharma Gesellschaft Fuer Die Entwicklung Und Vermarktung Pharmazeutischer Producte Mbh||Pharmaceutical composition|
|US5972906||19 Jul 1995||26 Oct 1999||Hyal Pharmaceutical Corporation||Treatment of mucous membrane disease, trauma or condition and for the relief of pain thereof|
|US5972932 *||24 Mar 1997||26 Oct 1999||Eli Lilly And Company||Anesthetic method and composition|
|US5976573||3 Jul 1996||2 Nov 1999||Rorer Pharmaceutical Products Inc.||Aqueous-based pharmaceutical composition|
|US5989535||15 Aug 1997||23 Nov 1999||Soma Technologies||Polymeric bioadhesive emulsions and suspensions and methods of treatment|
|US5993846||21 Apr 1998||30 Nov 1999||Pharmos Corporation||Bioadhesive emulsion preparations for enhanced drug delivery|
|US6031007 *||1 Apr 1997||29 Feb 2000||Astra Ab||Pharmaceutical composition with anaesthetic effect|
|WO2000003716A1||15 Jul 1999||27 Jan 2000||Kolesnikov Yuri||Topical compositions comprising an opioid analgesic and an nmda antagonist|
|1||Atanassoff et al., 1997, "The Effect of Intradermal Administration of Lidocaine and Morphine on the Response to Thermal Stimulation", Anest. Analg. 84:1340-1343.|
|2||de Vries et al., 1991, "Developments in Buccal Drug Devlivery", Critical Reviews in Therapeutic Drug Carrier Systems, 8(3):271-303.|
|3||Harris et al., 1992, "Drug Dellivery via the Mucous Membranes of the Oral Cavity", J. of Pharm. Sciences 81(1):1-10.|
|4||Juninger HE, 1991, "Mucoadhesive Hydrogels", Pharm. Ind. 53(11):1056-1065.|
|5||Kolesnikov Y, 1999, "Topical opioids in mice: analgesia and reversal of tolerance by a topical N-methyl-D-aspartate antagonist", J Pharmacol Exp Ther. 290(1):247-52.|
|6||Kolesnikov Y, 2000, "Analgesic synergy between topical lidocaine and topical opioids", J Pharmacol Exp Ther. 295(2):546-51.|
|7||Lehr et al., 1992, "Visualization studies of the mucoadhesive interface", J. of Controlled Release, 18:249-260.|
|8||Likar R, 1998, "Peripheral morphine analgesia in dental surgery", Pain. 76(1-2):145-50.|
|9||Lockhart et al., 1981, "Alterations in the Oral Mucosa Caused by Chemotherapeutic Agents", J. Dermatol. Surg. Oncol. 7(12):1019 1025.|
|10||McQuinn et al., 1995, "Sustained oral muscosal delivery in human volunteers of buprenorphine from a thin non-eroding mucoadhesive polymeric disk", J. of Controlled Release 34:243-250.|
|11||Rossi et al., 1994, "mu and delta opioid synergy between the periaqueductal gray and the rostro-ventral medulla", Brain Res. 665:85-93.|
|12||Rossi et al., 1994, "μ and δ opioid synergy between the periaqueductal gray and the rostro-ventral medulla", Brain Res. 665:85-93.|
|13||Rottenberg et al., 1991, "Development and Testing of Bioadhesive, Fluoride-containing Slow Release Tablets for Oral Use", J. Pharm. Pharmacol. 43:457-464.|
|14||Salto et al., 1998, "Interaction of Intrathecally Infused Morphine and Lidocaine in Rats (Part II)", Anesthesiology 89:1464-1470.|
|15||Sonis et al., "Oral Complications of Cancer Chemotherapy in Pediatric Patients", 122-128.|
|16||Sonis et al., 1990, "An animal model for mucositis induced by cancer chemotherapy", Oral Surg. Oral Med. Oral Pathol. 69:437-44.|
|17||Sonis et al., 1991, Prevention and Management of Oral Mucositis Induced by Antineoplastic Therapy 5:11-22.|
|18||Stein et al., 1997, "Peripheral morphine analgesia", Pain. 71(2):119-21.|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US6602490 *||4 Mar 2002||5 Aug 2003||Richard A. Cloonan||Dental cleaning formulation and manufacturing process|
|US7273889 *||25 Sep 2002||25 Sep 2007||Innovative Drug Delivery Systems, Inc.||NMDA receptor antagonist formulation with reduced neurotoxicity|
|US7501452||29 Nov 2006||10 Mar 2009||Endo Pharmaceuticals Inc.||Treatment of xerostomia|
|US7766658||30 Nov 2004||3 Aug 2010||Align Technology, Inc.||Systems and methods for intra-oral diagnosis|
|US7811606||16 Apr 2003||12 Oct 2010||Dey, L.P.||Nasal pharmaceutical formulations and methods of using the same|
|US7947508||31 Oct 2007||24 May 2011||Align Technology, Inc.||Systems and methods for intra-oral diagnosis|
|US7972626||14 Oct 2005||5 Jul 2011||Merck Patent Gmbh||Fluticasone propionate nasal pharmaceutical formulations and methods of using same|
|US7972627||14 Oct 2005||5 Jul 2011||Merck Patent Gmbh||Beclomethasone dipropionate monohydrate nasal pharmaceutical formulations and methods of using the same|
|US7973008||18 Sep 2009||5 Jul 2011||Dmi Biosciences, Inc.||Metal-binding compounds and uses therefor|
|US8017728||2 Nov 2009||13 Sep 2011||David Bar-Or||Metal-binding compounds and uses therefor|
|US8075309||31 Oct 2007||13 Dec 2011||Align Technology, Inc.||Systems and methods for intra-oral drug delivery|
|US8129364||14 Oct 2005||6 Mar 2012||Dey Pharma, L.P.||Formulations and methods for treating rhinosinusitis|
|US8158154||31 Oct 2007||17 Apr 2012||Dey Pharma, L.P.||Nasal pharmaceutical formulations and methods of using the same|
|US8188215||4 May 2011||29 May 2012||David Bar-Or||Metal-binding compounds and uses therefor|
|US8263047||29 Sep 2005||11 Sep 2012||Wickenhauser Alan J||Topical anesthetic for dental procedures|
|US8263548||4 May 2011||11 Sep 2012||Dmi Biosciences, Inc.||Metal-binding compounds and uses therefor|
|US8309061||12 Mar 2005||13 Nov 2012||Dey Pharma, L.P.||Formulations and methods for treating rhinosinusitis|
|US8324192||9 Nov 2006||4 Dec 2012||The Regents Of The University Of California||Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract|
|US8387798||17 May 2012||5 Mar 2013||Abdulmohsen E. A. H. Al-Terki||Mutiple oral and nasal surgical procedures method and kit|
|US8425892||28 Apr 2003||23 Apr 2013||Columbia Laboratories, Inc.||Extended, controlled-release pharmaceutical compositions using charged polymers|
|US8439674||13 Dec 2011||14 May 2013||Align Technology, Inc.||Systems and methods for intra-oral drug delivery|
|US8497258||12 Nov 2008||30 Jul 2013||The Regents Of The University Of California||Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract|
|US8574552||21 Jul 2006||5 Nov 2013||Alpex Pharma S.A.||Solid dosage formulations of narcotic drugs having improved buccal adsorption|
|US8623334||10 Sep 2012||7 Jan 2014||Alan J. Wickenhauser||Topical anesthetic|
|US8663695||31 Oct 2007||4 Mar 2014||Mylan Specialty L.P.||Formulations and methods for treating rhinosinusitis|
|US8679545||12 Nov 2008||25 Mar 2014||The Regents Of The University Of California||Topical corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract|
|US8701671||6 Feb 2012||22 Apr 2014||Joseph E. Kovarik||Non-surgical method and system for reducing snoring|
|US8784870||21 Jul 2009||22 Jul 2014||Otonomy, Inc.||Controlled release compositions for modulating free-radical induced damage and methods of use thereof|
|US8865692||12 Nov 2008||21 Oct 2014||Meritage Pharma, Inc||Compositions for the treatment of gastrointestinal inflammation|
|US8912174||4 Sep 2003||16 Dec 2014||Mylan Pharmaceuticals Inc.||Formulations and methods for treating rhinosinusitis|
|US8968710||6 Jan 2014||3 Mar 2015||Alan J. Wickenhauser||Topical anesthetic|
|US8975243||30 Nov 2012||10 Mar 2015||The Regents Of The University Of California||Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract|
|US9050368||12 Nov 2008||9 Jun 2015||Meritage Pharma, Inc.||Corticosteroid compositions|
|US9119863||8 Jul 2013||1 Sep 2015||The Regents Of The University Of California||Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract|
|US9132087||21 Apr 2009||15 Sep 2015||Otonomy, Inc.||Auris formulations for treating otic diseases and conditions|
|US9180126||8 Feb 2012||10 Nov 2015||Mylan Specialty L.P.||Formulations and methods for treating rhinosinusitis|
|US20030095945 *||29 Apr 2002||22 May 2003||Children's Hospital Los Angeles||Bone hemostasis method and materials|
|US20030114394 *||24 Oct 2002||19 Jun 2003||Levine Howard L.||Vaginally administered anti-dysrhythmic agents for treating pelvic pain|
|US20030124190 *||21 Jan 2003||3 Jul 2003||Epicept, Inc.||Methods and compositions for treating pain of the mucous membrane|
|US20030158111 *||19 Nov 2002||21 Aug 2003||David Bar-Or||Methods and products for oral care|
|US20030211071 *||28 Apr 2003||13 Nov 2003||Bologna William J.||Extended, controlled-release pharmaceutical compositions using charged polymers|
|US20040059003 *||25 Sep 2002||25 Mar 2004||Innovative Drug Delivery Systems, Inc.||NMDA receptor antagonist formulation with reduced neurotoxicity|
|US20040141949 *||4 Dec 2003||22 Jul 2004||Rosenthal Gary J.||Treatment of mucositis|
|US20040208830 *||16 Apr 2003||21 Oct 2004||Imtiaz Chaudry||Nasal pharmaceutical formulations and methods of using the same|
|US20040208831 *||16 Apr 2003||21 Oct 2004||Imtiaz Chaudry||Nasal pharmaceutical formulations and methods of using the same|
|US20040209852 *||4 Sep 2003||21 Oct 2004||Imtiaz Chaudry||Formulations and methods for treating rhinosinusitis|
|US20040213828 *||23 Apr 2003||28 Oct 2004||Smith David J.||Pain relief lollipop compositions and methods|
|US20050002876 *||7 May 2004||6 Jan 2005||Yukl Richard L.||Oral care methods and products|
|US20050018268 *||14 Jun 2004||27 Jan 2005||Yoshinori Hayashi||Optical scanner and image forming apparatus|
|US20050180925 *||12 Mar 2005||18 Aug 2005||Dey, L.P.||Formulations and methods for treating rhinosinusitis|
|US20050256193 *||20 Jul 2005||17 Nov 2005||Boehringer Ingelheim Pharma Gmbh & Co. Kg||Ambroxol for the treatment of painful conditions in the mouth and pharyngeal cavity|
|US20050266090 *||10 May 2005||1 Dec 2005||Ales Prokop||Nanoparticular targeting and therapy|
|US20060039871 *||14 Oct 2005||23 Feb 2006||Merck Patent Gmbh||Nasal pharmaceutical formulations and methods of using the same|
|US20060051299 *||14 Oct 2005||9 Mar 2006||Merck Patent Gmbh||Nasal pharmaceutical formulations and methods of using the same|
|US20060051300 *||14 Oct 2005||9 Mar 2006||Merck Patent Gmbh||Formulations and methods for treating rhinosinusitis|
|US20060115782 *||30 Nov 2004||1 Jun 2006||Chunhua Li||Systems and methods for coating a dental appliance|
|US20060115785 *||30 Nov 2004||1 Jun 2006||Chunhua Li||Systems and methods for intra-oral drug delivery|
|US20060116561 *||30 Nov 2004||1 Jun 2006||Tricca Robert E||Systems and methods for intra-oral diagnosis|
|US20060252010 *||3 Aug 2005||9 Nov 2006||Sunnen Gerard V||Sodium chloride pad for treatment of dental conditions|
|US20070014860 *||22 Sep 2006||18 Jan 2007||Rosenthal Gary J||Treatment of esophagitis|
|US20070014861 *||22 Sep 2006||18 Jan 2007||Rosenthal Gary J||Treatment of proctitis|
|US20070020187 *||21 Jul 2006||25 Jan 2007||Alpex Pharma S.A.||Solid dosage formulations of narcotic drugs having improved buccal adsorption|
|US20070071802 *||29 Sep 2005||29 Mar 2007||Wickenhauser Alan J||Topical anesthetic for dental procedures|
|US20070071824 *||29 Sep 2006||29 Mar 2007||Rosenthal Gary J||Treatment of mucositis using N-acetylcysteine|
|US20070128284 *||29 Nov 2006||7 Jun 2007||Endo Pharmaceuticals Inc.||Treatment of xerostomia|
|US20070224267 *||21 May 2007||27 Sep 2007||Uwe Pschorn||Ambroxol for the treatment of painful conditions in the mouth and pharyngeal cavity|
|US20070231396 *||29 Mar 2006||4 Oct 2007||Ray Charles D||Medication spray formulation|
|US20070248657 *||25 Apr 2006||25 Oct 2007||Smith David J||Multi-compartment transdermal pain control device|
|US20080041367 *||16 Aug 2007||21 Feb 2008||Mermelstein Fred H||NMDA Receptor Antagonist Formulation With Reduced Neurotoxicity|
|US20080050442 *||31 Oct 2007||28 Feb 2008||Dey, L.P.||Nasal pharmaceutical formulations and methods of using the same|
|US20080058295 *||31 Oct 2007||6 Mar 2008||Dey, L.P.||Nasal pharmaceutical formulations and methods of using the same|
|US20080058296 *||31 Oct 2007||6 Mar 2008||Imtiaz Chaudry||Formulations and methods for treating rhinosinusitis|
|US20080119698 *||31 Oct 2007||22 May 2008||Tricca Robert E||Systems and methods for intra-oral diagnosis|
|US20080182841 *||4 Sep 2007||31 Jul 2008||Levine Howard L||Vaginally administered anti-dysrhythmic agents for treating pelvic pain|
|US20080214664 *||29 Feb 2008||4 Sep 2008||Combe Incorporated||Anesthetic spray composition|
|US20080248090 *||12 Jun 2008||9 Oct 2008||Sunnen Gerard V||Graduated concentration sodium chloride patches for the treatment of dental conditions|
|US20080293007 *||31 Oct 2007||27 Nov 2008||Chunhua Li||Systems and methods for intra-oral drug delivery|
|US20080305149 *||6 Jun 2008||11 Dec 2008||Thomas Hirt||Mucoadhesive vesicles for drug delivery|
|US20090123550 *||12 Nov 2008||14 May 2009||Meritage Pharma, Inc.||Corticosteroid compositions|
|US20090123551 *||12 Nov 2008||14 May 2009||Meritage Pharma, Inc.||Gastrointestinal delivery systems|
|US20090131386 *||12 Nov 2008||21 May 2009||Meritage Pharma, Inc.||Compositions for the treatment of inflammation of the gastrointestinal tract|
|US20090137540 *||12 Nov 2008||28 May 2009||Meritage Pharma, Inc.||Compositions for the treatment of gastrointestinal inflammation|
|US20090149433 *||12 Nov 2008||11 Jun 2009||Meritage Pharma, Inc.||Compositions for the treatment of inflammation of the gastrointestinal tract|
|US20090181099 *||12 Nov 2008||16 Jul 2009||The Regents Of The University Of California, San Diego||Topical corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract|
|US20090264392 *||20 Apr 2009||22 Oct 2009||Meritage Pharma, Inc.||Treating eosinophilic esophagitis|
|US20100022661 *||28 Jan 2010||Otonomy, Inc.||Controlled release compositions for modulating free-radical induced damage and methods of use thereof|
|US20100143449 *||29 Feb 2008||10 Jun 2010||Yuri Kolesnikov||Analgesic composition of topically applied nonsteroidal antiinflammatory drugs and opioids|
|US20100216754 *||26 Aug 2010||Meritage Pharma, Inc.||Compositions for the treatment of inflammation of the gastrointestinal tract|
|US20100221313 *||30 Nov 2009||2 Sep 2010||Innovative Pharmaceuticals, Llc||Transdermal reservoir patch|
|US20100240749 *||23 Sep 2010||Combe Incorporated||Anesthetic spray composition|
|US20110097401 *||28 Apr 2011||Meritage Pharma, Inc.||Methods for treating gastrointestinal disorders|
|US20110117175 *||1 Sep 2010||19 May 2011||Rosenbaum Richard J||Sweet analgesic for use in medical procedures or treatments|
|US20110195988 *||11 Aug 2011||Special Products Limited||Pharmaceutical Composition|
|US20110212902 *||1 Sep 2011||David Bar-Or||Metal-binding compounds and uses therefor|
|US20110212903 *||1 Sep 2011||David Bar-Or||Metal-binding compounds and uses therefor|
|US20140371305 *||14 Jun 2013||18 Dec 2014||Professional Compounding Centers Of America||Mupirocin Antibiotic Composition|
|EP1749528A1||5 Aug 2005||7 Feb 2007||Pharma C S.A.||Pharmaceutical combinations containing a mu opioid agonist and an inhibitor of NO production|
|U.S. Classification||424/434, 514/817, 514/818, 424/486, 424/443|
|International Classification||A61K31/445, A61K47/34, A61K31/451, A61P43/00, A61K31/167, A61P41/00, A61P1/02, A61P23/02, A61P29/00, A61P17/02, A61K31/4748, A61K9/12, A61P25/04, A61K31/485, A61K45/06, A61K9/00|
|Cooperative Classification||Y10S514/818, Y10S514/817, A61K31/485, A61K31/445, A61K9/0043, A61K45/06, A61K9/006|
|European Classification||A61K31/485, A61K31/445, A61K9/00M18D, A61K9/00M14, A61K45/06|
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